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Chapter 7 Anticoagulant therapy

118

occur: unusual pain, swelling, discomfort, unusual

or prolonged bleeding, unusual or ‘easy’ bruising,

dark urine, black stools, severe headache, confu-

sion, vision changes, dizziness, fainting, seizures,

weakness or numbness. Dose reductions may be

required in patients with hepatic impairment and

this group of anticoagulants may be less suita-

ble than unfractionated heparins in patients with

renal impairment.

Hirudin

This anticoagulant is a naturally occurring protein

found in the salivary glands of medicinal leeches.

Rather than potentiating the effects of antithrom-

bin III, hirudin is a specific inhibitor of thrombin.

Analogues can now be produced synthetically by

recombinant techniques. The drug bivalirudin is

an analogue used in unstable angina and in the

management of ST segment elevation myocardial

infarction.

Coumarins

The coumarins (warfarin, acenocoumarol and

phenindione) antagonize the action of vitamin K

and so reduce the production of prothrombin and

clotting factors VII, IX and X. The onset of action

of warfarin takes several days, as the plasma fac-

tors that have been manufactured prior to com-

mencement of warfarin take time before they are

eliminated from the body.

Warfarin is the most common oral anticoag-

ulant and is given in tablet form, as it is easily

absorbed by the GI tract. One of the problems with

warfarin is that it is strongly attracted to plasma

proteins. These proteins normally help maintain

the osmotic intravascular pressure. However, as

warfarin is bound to these, potential problems

occur with stabilizing the dose, treating elderly

people and giving other drugs, such as aspirin,

that compete for binding sites on the plasma pro-

teins. The peak pharmacological concentration

takes approximately 48 hours. The effectiveness

of the drug is measured by a blood test known as

the prothrombin time, now expressed as an inter-

national normalized ratio or INR. This laboratory

test measures the time it takes for blood to clot

and compares it to an average. The higher the INR

value, the longer it takes for blood to clot.

Clinical tip

While taking warfarin, patients will

have regular blood tests to establish their

INR. For patients diagnosed with atrial

fibrillation, the target INR typically should

be between 2.0 and 3.0. Patients who have

been fitted with mechanical hear t valves

should have an INR around 3.0 or 4.0.

Warfarin crosses the placenta and therefore

should not be given in the first 3 months of preg-

nancy, as fetal abnormalities may ensue. Intrac-

ranial bleeding in the baby may occur during

delivery and mothers should be immediately

offered prophylaxis with vitamin K.

As with heparin, the most obvious side-effect is

bleeding. This may be due to deliberate or acci-

dental overdose or to the interaction of warfarin

with other drugs leading to an increase in its anti-

coagulant effect. If bleeding does occur, the drug

should be withdrawn. The anticoagulant effects

may be reversed by giving fresh frozen plasma or

vitamin K (phytomenadione) intravenously.

A complication of warfarin is a condition

referred to as calciphylaxis, which occurs when

calcium collects in the small vessels in the skin

and produces painful rashes, blood clots and sores.

This may seem paradoxical, as warfarin is given

for its anticoagulant effect. The MHRA/CHM issued

a warning about this in 2016 after an increase in

reports of its occurrence and the likelihood of it

developing in patients with renal disease.

A variety of disease processes and drugs can

modify the action of warfarin. Some potentiate

the anticoagulant actions, while others lessen the

effect of the drug. Liver disease, thyrotoxicosis

and fever may all interfere with the natural manu-

facture of clotting factors by the body. If warfarin

is given in these circumstances, there will be an

increase in anticoagulation. Some drugs can also

lead to exaggerated anticoagulant effects if given

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Chapter 7 Anticoagulant therapy

119

in conjunction with warfarin. Drugs such as cime-

tidine can reduce the breakdown of warfarin by

liver enzymes. NSAIDs compete successfully with

warfarin for a place on plasma proteins, therefore

leaving more active drugs in the plasma. Antibiot-

ics are another group of drugs that need careful

thought before prescribing because broad spec-

trum antibiotics and some sulfonamides depress

the body’s natural ability to manufacture vitamin

K by intestinal flora.

Anticoagulant effects can also be lessened in

some circumstances. Hypothyroidism is asso-

ciated with a slower breakdown of coagulation

factors. Foods and commercially produced prepa-

rations containing high vitamin K content will

reduce the warfarin effect. Also, drugs that cause

the enzymes in the liver that break down warfarin

to increase, such as carbamazepine, will have the

same effect. Warfarin is a complex drug that needs

to be monitored carefully, and good discharge

advice is crucial.

Antiplatelet drugs

Earlier in this chapter we discussed the impor-

tance of the formation of a platelet plug in hae-

mostasis. Drugs that affect this important process

have strong therapeutic value. Probably the most

common and popular in this category is aspirin.

Aspirin

In discussing the platelet plug, we highlighted two

important substances that work in opposing ways

on the stickiness of blood. These are thrombox-

ane, which increases the stickiness and prostacy-

clin, which decreases the stickiness. Aspirin alters

the fine balance between these two prostaglan-

dins. It reduces both substances in the body but

because prostacyclin can be made by endothelial

cells and thromboxane levels require 7–10 days for

new platelets to be formed, prostacyclin levels are

improved at the expense of thromboxane. There-

fore, an anticoagulant effect is achieved. Aspirin

does have a few serious side-effects, but these are

limited as it is given at a low dose for its anticoag-

ulant effect. A dose of 75mg daily is sufficient to

achieve anticoagulation, as opposed to a dose of

300mg daily which would be prescribed in its role

as an analgesic. Aspirin may be given for a num-

ber of conditions, including coronary thrombosis,

angina and following transient ischaemic attacks

or stroke.

Clopidogrel

This is a powerful antiplatelet medicine used for

a variety of conditions, including coronary artery

disease, peripheral vascular disease and cerebro-

vascular disease.

The drug works by blocking receptor sites

on the platelets. This means that when fibrin is

formed it cannot stick to the platelet, and so the

plug to block bleeding does not occur as the plate-

lets cannot clump together. It is sometimes used

alongside aspirin.

Clopidogrel can be given orally and is normally

prescribed at 75mg once per day. It is a pro-drug

activated by the liver when it first passes through.

Once the drug has been activated, its elimination

half-life is 8 hours. The drug reaches a peak level in

Clinical tip

Many hospitals provide patients who

receive warfarin with documentation explain-

ing their therapy, detailing why they are

taking the drug, its side-effects, what an

INR means and the importance of taking

the medication at the same time each day.

Advice is also essential regarding some

lifestyle changes that will need to be made to

ensure the patient gets the greatest bene-

fits from taking the drug. Consequently, the

patient should receive advice on healthy eat-

ing, consumption of alcohol and prevention of

injury and/or bleeding while taking warfarin.

Finally, the patient should have information

regarding dental treatment and what to do

in the event of an injury or if bleeding takes

place. The patient will also be given an antico-

agulant card to remind them of the dose they

are taking or to be prescribed in the future by

either the anticoagulant clinic or the GP.

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Chapter 7 Anticoagulant therapy

120

the blood after one hour. It should be used with cau-

tion in patients with renal or hepatic impairment.

The drug triggers the plasma protein plasmino-

gen to liberate plasmin, which breaks down fibrin,

so dissolving the clot. The drug is extracted from

bacteria called haemolytic streptococci. It has a

short half-life of less than 20 minutes and is there-

fore given by continuous IV infusion. Most people

will have developed antibodies to streptococcal

proteins, so often a large bolus dose is used to

start therapy, followed by a maintenance infu-

sion. As antibodies form against the streptococcal

proteins, it is usually best not to provide a further

treatment with the drug until a year has elapsed.

Also, due to the body’s immune response, other

drugs, such as chlorphenamine or hydrocortisone,

may be given to reduce any allergic response.

Clinical tip

Haemorrhage is by far the most

common side-effect of this class of drug.

You should ask the patient to report any

unusual bleeding or bruising. Another

side-effect is neutropenia (low level of a

type of white blood cell called a neutrophil

in the bloodstream). Therefore, you should

encourage the patient to contact their

doctor if they experience fever, signs of

infection or extreme tiredness.

Clinical tip

In practice, you will often hear fibrino-

lytic drugs referred to as ‘clot busters’.

Clinical tip

The main risk of streptokinase is

haemorrhage. This normally occurs near

the injection site or a site of recent trauma.

You must constantly monitor the site of

administration and document any untoward

signs and symptoms. It is contraindicated

in patients in whom it may cause bleeding,

such as those with peptic ulcer. Therefore,

it is important to ask the patient about their

past medical history before administration

of this drug.

Fibrinolytic drugs

These drugs mimic the body’s own ability to dis-

solve blood clots. A number of drugs are used in

practice that dissolve clots in order to allow free

passage of blood back to an area that has been

starved of blood (i.e. ischaemic). Their main use

is in patients who have had acute myocardial

infarction following blockages of the coronary

artery, but these can also be given to patients who

have had an ischaemic stroke caused by throm-

bus formation.

Streptokinase

This drug is used to dissolve the fibrin of blood

clots, especially those that occur in the heart and

lungs. Acute myocardial infarction results from

blockage of a coronary artery, which results in

an area of heart muscle being deprived of blood.

Streptokinase is used to break down such clots in

the coronary vessels.

Alteplase

This drug is derived from human tissue plasminogen

activator, and thus directly converts plasminogen to

plasmin. It binds strongly with fibrin and digests clots

in coronary arteries at least as well if not better than

streptokinase. It has the advantages of not causing

immune responses and, having a greater attraction

to fibrin-bound plasminogen rather than circulating

plasma fibrinogen, is said to be ‘clot selective’. As

with streptokinase, the drug has a short half-life and

is therefore given by IV infusion. Although alteplase

is less likely to cause bleeding, it is contraindicated

in pregnancy, uncontrolled hypertension, haemor-

rhagic cerebrovascular disease and active internal

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Chapter 7 Anticoagulant therapy

121

bleeding. If bleeding occurs, it can be treated with

tranexamic acid. This stops plasminogen activation

and therefore prevents clots dissolving. The patient

may also be given fresh plasma or coagulation fac-

tors.

Direct acting anticoagulant

drugs (DOACs)

Rivaroxaban and apixaban are members of the

class of drugs known as oral factor Xa inhibitors.

By inhibiting factor Xa, thrombin production and

the formation of clots are ultimately inhibited.

Currently, these drugs are licensed for the preven-

tion of venous thromboembolism (VTE) in adults

undergoing elective hip or knee replacement sur-

gery, at a fixed dose of 10mg daily. They can also

be used for treatment of deep vein thrombosis

(DVT), and pulmonary embolism as well as in ACS.

These drugs have predictable pharmacokinet-

ics, with little variation of plasma concentration

with age, weight or renal function following a

fixed dose. With a fixed dose, a wide therapeutic

window, few drug interactions and predictable

pharmacodynamics, no routine monitoring of

coagulation parameters is required. They are well

absorbed from the gut and maximum inhibition of

factor Xa occurs 4 hours after a dose. The effects

last 8–12 hours, but factor Xa activity does not

return to normal within 24 hours, so once-daily

dosing is possible.

The anticoagulant dabigatran is a member of

the class of drugs known as direct thrombin inhib-

itors. It offers an alternative to warfarin as an

orally administered anticoagulant, since it does

not require frequent blood tests for INR monitoring

while offering similar results in terms of efficacy.

Dabigatran is a pro-drug with no anticoagulant

activity; once absorbed, it is rapidly converted

by enzymes in the GI tract, blood and liver into

dabigatran, a thrombin inhibitor. Although costly,

dabigatran has several potential advantages over

warfarin. The pharmacokinetics are quite pre-

dictable, simplifying dosing and eliminating the

need for frequent blood tests and monitoring. In

addition, the drug necessitates no dietary restric-

tions, although potential drug interactions include

those with quinidine, ketoconazole, amiodarone,

rifampicin and verapamil. Peak anticoagulation

effects occur between 30 minutes and 2 hours

after ingestion and dabigatran is primarily elimi-

nated by the kidneys.

Case studies

Olek Krupa is a 65-year-old widower and owns a roofing company. His aim is to retire

in a couple of years’ time, so he is increasingly leaving his sons to manage the business

while he enjoys more golfing holidays. He lives on his own but has a wide circle of friends. He en-

joys watching football and having a few pints at his local pub. He does this on a few nights or

afternoons in the week. He recently visited his GP for a check-up but prior to this had not seen

his doctor for a number of years. He was found to have high blood pressure, be overweight and to

have a heart condition for which the GP prescribed aspirin. Further to this, he was referred to his

local cardiologist, who recommended that he stop the aspirin in favour of commencing warfarin.

What advice would you give to Mr Krupa with regard to his warfarin therapy?

Mr Patel is a 70-year-old man who has been on warfarin for some years for his atrial fibrillation.

His condition had been well controlled by the warfarin and his regular blood tests had shown

that his INR readings reflected a time in the therapeutic range (TTR) of 74%. He has now been

referred to the surgeon by his GP since he has been displaying certain gastrointestinal signs and

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Chapter 7 Anticoagulant therapy

122

symptoms. Following his consultation with the consultant surgeon, he has been given a date for

an endoscopic removal of colonic polyps.

■ What is the difference in the modes of action of war farin and enoxaparin?

■ Mr Patel is anxious regarding this surgery and he asks you to tell him what will happen to his

warfarin therapy before, during and after the procedure. What do you tell him?

Bo Wong is a 72-year-old female who has a history of osteoarthritis. She has had a right total

hip replacement and is now ready for discharge. She has agreed to administer her own enoxapa-

rin at home for 4 weeks post-operatively to prevent deep vein thrombosis formation.

Your mentor has asked you to teach the lady how to do this, so she is confident. What instruc-

tions would you give her?

→

Key learning points

Introduction

▶

Blood clotting is a normal homeostatic mechanism.

▶

Haemostasis is divided into four processes: constriction of blood vessel, formation of platelet

plug, formation of fibrin clot and dissolving of the clot.

▶

Constriction of the vessel reduces blood flow.

▶

Constriction allows clotting factors to contact the damaged vessels.

▶

Formation of a platelet plug begins with exposure to collagen and elastin fibres.

▶

Platelets release thromboxane.

▶

The formation of a fibrin clot is a complex chain reaction triggered in one of two ways:

extrinsically or intrinsically.

▶

The clot dissolves more slowly than it was formed.

▶

Fibrin is dissolved by plasmin.

Blood clotting and the development of thrombosis

▶

Thrombosis is the formation of a clot in a vessel within the cardiovascular system, which

relates to or arises from a disease process.

▶

In arteries, the clot is usually associated with a build-up of fatty plaques (atherosclerosis).

▶

Acute coronary syndromes arise due to narrowing of the blood vessels supplying the heart

by these fatty plaques leading to thrombus formation.

Drugs that act on the clotting cascade

Heparin

▶

Heparin is a complex protein that cannot be given orally.

▶

It works by activating antithrombin III.

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Chapter 7 Anticoagulant therapy

123

▶

It stops the clotting cascade at the thrombin stage.

▶

The activated partial plasma thrombin time (aPPT) test is used to measure efficacy.

▶

Low molecular weight heparins are more predictable.

▶

They are given subcutaneously twice daily.

▶

Examples are tinzaparin and enoxaparin.

Enoxaparin

▶

Enoxaparin binds to and accelerates the activity of antithrombin III.

▶

The dose to prevent thromboembolism is 40mg subcutaneously once a day.

▶

The usual duration of administration is 6–11 days, but up to 14 days.

▶

To minimize irritation, use a different injection site for each dose.

▶

To minimize bruising, do not rub the injection site following administration.

▶

The patient should tell their doctor immediately if signs of bleeding occur.

Warfarin

▶

Warfarin is a vitamin K antagonist.

▶

It reduces the manufacture of a range of clotting factors.

▶

It takes several days to achieve its effects.

▶

It is highly protein bound.

▶

It is measured by the INR.

▶

Can cross placental barrier.

▶

Haemorrhage is a major side-effect.

▶

A number of disease processes and other drugs can potentiate or inhibit its action.

▶

Patients should be given detailed discharge advice.

Aspirin

▶

Aspirin alters the fine balance between thromboxane and prostacyclin.

▶

It is given in low dosages to limit side-effects.

▶

It is suitable for a number of conditions (e.g. coronary thrombosis).

Clopidogrel

▶

Stops fibrin attaching to platelets.

▶

Often given alongside low-dose aspirin.

▶

Haemorrhage is a common side-effect.

Streptokinase

▶

Dissolves fibrin.

▶

Liberates plasmin from plasminogen.

▶

One treatment is given per year.

▶

Risk of haemorrhage.

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Chapter 7 Anticoagulant therapy

124

Alteplase

▶

Converts plasminogen to plasmin.

▶

Does not cause immune response like streptokinase.

▶

Has to be given intravenously.

▶

Contraindicated in pregnancy, haemorrhagic cerebrovascular disease and internal bleeding.

Direct acting anticoagulant drugs

▶

Rivaroxaban and apixaban are oral factor Xa (Stuart-Prower) inhibitors.

▶

Dabigatran is an option for primary prevention of venous thromboembolic event.

→

Calculations

1. A doctor orders a patient to have 25,000 international units (iu) of heparin which is to

be given intravenously. On the ward you only have 5000iu of heparin in 1mL. How many mL

of heparin would you give?

2. A patient has been prescribed 300mg of aspirin. You have 75mg tablets. How many would

you need to administer?

3. The dose of tinzaparin for the treatment of deep vein thrombosis is 175 units per kg. The

injection is 20,000 units per mL. What dose would be required to treat a 60kg patient?

4. A doctor orders heparin 9000iu to be given subcutaneously twice daily. The ward stock only

consists of 10,000iu per mL. How many mL of heparin would you give?

5. Warfarin is available as 0.5mg, 1mg, 3mg and 5mg tablets. You need to administer a 7mg

dose. What is the least number of tablets you can give?

6. 20,000iu of heparin is added to 500mL of 0.9% saline. The dose prescribed is 200iu per

hour. Calculate the rate of the infusion in mL per hour.

7. You need to give 1mg of vitamin K orally. How many mL of a 10mg per mL vitamin K injection

would you give?

8. You have been asked to prepare a heparin syringe for intravenous infusion; 40mL of solution

is required, containing 500 units of heparin per mL. The heparin ampoules stocked on the

ward contain 5000 units per mL. What volume of heparin and saline would be required to

prepare the syringe?

9. You have a syringe of enoxaparin containing 150 mg per mL. How much is required to give a

90kg man a dose of 1.5mg per kg?

10. An anaesthetist prescribes a patient 2500iu of dalteparin sodium 2 hours prior to surgery,

2500iu 4–8 hours post-surgery and 5000iu daily for 5–10 days post-operatively. How many

mL from a vial containing 10,000iu per mL should be administered: (a) prior to surgery,

(b) after surgery and (c) the following day after surgery?

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Chapter 7 Anticoagulant therapy

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Multiple-choice questions

Try answering these multiple-choice questions to test what you have learned from reading this

chapter. You can check your answers at the end of this book.

1. Haemophilia A is caused by a lack of which clotting factor?

a) Factor X

b) Factor VII

c) Factor VIII

d) Factor III

2. Where in the body is heparin normally manufactured?

a) Liver

b) Kidney

c) Spleen

d) Pancreas

3. What substance does heparin activate in order to produce its anticoagulant effect?

a) Antithrombin

b) Thromboxane

c) Prostacyclin

d) Fibrinogen

4. What drug reverses the effects of heparin?

a) Warfarin

b) Aspirin

c) Vitamin K

d) Protamine sulphate

5. How does warfarin work?

a) Decreases the amount of circulating platelets

b) Increases the amount of antithrombin

c) Antagonizes vitamin K

d) Increases the amount of prostacyclin

6. Which of the following drugs is a low molecular weight heparin?

a) Clopidogrel

b) Tinzaparin

c) Dipyridamole

d) Hirudin

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Chapter 7 Anticoagulant therapy

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